Inflammation is a general term for the mechanisms by which the body reacts to infection, irritation and other injury, mobilizing components of the immune system. Polymorphonuclear cells are recruited in the early stages of inflammation, and migrate to the site of inflammation. Chemokines and their receptors, together with other chemoattractants, are key mediators for PMN migration. Examples of chemoattractants are IL-8 and LTB4, which by binding to their receptors CXCR1/CXCR2 and BLT1, respectively, play a crucial role in the recruitment of PMN to the site of inflammation. Importantly, inflammation plays a role in numerous conditions, not only diseases normally classified as inflammatory diseases.
Ischemia is an absolute or relative shortage of the blood supply to an organ that results in tissue damage because of a lack of oxygen and nutrients. The heart, the brain, and the kidneys are among the organs that are the most sensitive to inadequate blood supply. Different treatment strategies are used depend on the organs involved and the cause of ischemia. One example is, after an acute heart ischemia (myocardial infarction), either a thrombolytic therapy or primary percutaneous coronary intervention has to be used to restore blood flow (myocardial reperfusion) in the infarct-related coronary artery. However, the restoration of blood after an ischemic episode causes the death of cardiac myocytes that were viable immediately before myocardial reperfusion. This myocardial injury is termed lethal reperfusion injury which increases the final size of myocardial infarct. Myocardial ischemia and reperfusion injury are believed to be associated with inflammatory reactions involving various types of cells and cytokines (Entman and Smith 1994).
Another example is stroke, and in particular ischemic stroke. In an ischemic stroke, blood supply to one or more parts of the brain is decreased, leading to dysfunction and necrosis of the brain tissue in those parts. There are several underlying causes for an ischemic stroke: thrombosis (obstruction of a blood vessel by a blood clot forming locally), embolism (obstruction of a blood vessel due to an embolus formed elsewhere in the body), systemic hypoperfusion (general decrease in blood supply, e.g. as a consequence of shock) and venous thrombosis.
Embolism is a serious condition which can lead to limited blood supply to organs or tissues, downstream from the embolus. Embolism, mentioned above as one causative factor in stroke, is known to cause obstruction in other organs, frequently in the lungs, kidneys, or liver, but also in the lower limbs. An embolus can form spontaneously, for example when plack is dislocated from the walls of a blood vessel and travels in the blood stream. Emboli may also form as a result of trauma, for example fat emboli from complicated fractures or blood clots (thrombi) from the site of haemorrhage. Patients undergoing surgery are also at risk, as both thrombi and fat emboli may form during the surgical intervention. Also immobility, obesity and cancer are risk factors, known to be associated with embolism.
Mesenteric ischemia is a medical condition in which inflammation and injury of the small intestine result from inadequate blood supply. Causes of the reduced blood flow can include changes in the systemic circulation (e.g. low blood pressure) or local factors such as constriction of blood vessels or a blood clot. Other intestinal disorders and conditions potentially leading to ischemia include ileus, distention, invagination, and volvolus, where abnormal orientation of the intestines, disruption of the peristaltic movement, and other conditions can lead to reduced blood flow, inflammation, and eventually ischemia. For example ileus may increase adhesion formation, because intestinal segments are in prolonged contact, allowing fibrous adhesions to form, and intestinal distention can cause serosal injury and ischemia. Such disorders can arise as a result of surgical intervention, either during the surgery or during recovery, as a result of trauma, burns, shock or various etiology etc and may lead to multiple organ failure.
Polymorphonuclear cells (PMNs), in particular polymorphonuclear neutrophils, which constitute the majority of the blood leukocytes are drawn into the infarct zone by chemoattractants during the first 6 hours of myocardial reperfusion, and during the next 24 hours they migrate into the myocardial tissue. This process is facilitated by cell adhesion molecules. The neutrophils cause vascular plugging and release degradative enzymes and reactive oxygen species (Vinten-Johansen J, 2004). Therefore neutrophils are the primary target for the purpose of the treatment or prevention of inflammation. Several interventions were aimed at reducing neutrophils from the infarct area during myocardial reperfusion e.g. leukocyte-depleted blood, antibodies against the cell adhesion molecules, and pharmacologic inhibitors of complement activation. However, the corresponding clinical studies have not shown any meaningful cardioprotective effect of such interventions (Reviewed in Yellon, 2007).
PMN accumulation and activation has been shown to play a central role in the pathogenesis of a wide range of disease states as diverse as rheumatoid arthritis, atherosclerosis, ulcerative colitis, psoriasis, and ischemic damage. Hence the elucidation of endogenous regulatory mechanisms that can control neutrophil functions are of considerable therapeutic interest. Extensive efforts have been spent on identifying drug candidates, and one approach is represented by the use of peptide compounds, which bind to the αM integrin I-domain and inhibit its complex formation with proMMP-9, thereby preventing neutrophil migration (See e.g. WO2004/110477)
Another approach is the use of lipoxin and lipoxin derivatives, small lipophilic compounds which have been shown to inhibit leukocyte recruitment and PMN infiltration in animal models of inflammation (See e.g. WO2000/055109).
Yet another approach is the use of antibodies. In the early 1990-ties, a potent CD47-specific antibody (Ab), C5/D5, was identified that was capable of inhibiting PMN migration across vascular endothelium, collagen-coated filters and intestinal epithelium without inhibiting β2 integrin-mediated adhesion (Parkos, et al., 1996). At the same time, it was shown that anti-CD47 also inhibited PMN migration across endothelial monolayers (Cooper, et al., Proc Natl Acad Sci USA, 92: 3978, 1995). Subsequent studies with CD47 knockout mice have confirmed the importance of CD47 in PMN migration in vivo suggesting that CD47 plays a role in regulating the rate of PMN recruitment to sites of infection. (Lindberg et al., 1996).
Transplantation is another application where the consequences of reperfusion ischemia must be considered. Transplantation means the transfer of cells, tissue or parts of organs or entire organs from one location to another. Transplants can be autologous, so called autografts, where mainly cells are taken from an individual and given back to that same individual. More frequently, the term transplant is used for cells, tissue or organs taken from one person, the donor, and given to another person, the recipient. Kidney transplants are the most commonly performed. Transplants of the heart, liver and lungs are also regularly carried out. As medicine advances, other vital organs including the pancreas and small bowel are also being used in transplants. Tissue such as corneas, heart valves, skin and bone can also be donated.
For practical reasons, a transplant needs to be stored outside the body for a period of time, to allow for transport, functional testing, tissue typing and matching the donor and the recipient. Since the advent of transplantation, organs to be transplanted have been kept in cold ischemic storage. Although this method was intended to help reduce the extent of organ damage during transport, significant damage still occurs. The more time that passes, the more serious damage. Different technical and chemical solutions have been proposed. However, as the number of persons in need of a transplant far exceeds the number of donors, and as the procedure is very complicated, costly and stressful for all parties, there remains a need for improvements that increase the chance of a successful transplantation. Minimizing organ damage during storage and transport is an important issue.
WO 2005/080568 concerns the use of NF-kB inhibiting compounds for the prevention or reduction of the extent of secondary ischemic damage in a mammal. The NF-kB inhibiting compounds are chosen from the group consisting of: an antisense NF-KB p65 subunit oligonucleotide; a dominant-negative form of the NF-KB p65 subunit; a decoy; ribosome inhibitors; enzymatic RNA against NF-KB p65; and siRNA constructs.
WO 2007/030580 concerns methods of protecting cells against cytotoxic insult, involving the administration of a composition including an agent that binds to and activates a Toll-like receptor to a subject, optionally in combination with administering an ASIC inhibitor. The methods are stated to be applicable to the protection of neural and non-neural cells. For example, methods of protecting a neural cell against excitotoxic brain injury are provided. Methods for preparing medicaments for the prophylactic treatment of excitotoxic injury, ischemia and/or hypoxia are also provided.
WO 2007/030581 is a parallel application to the above WO 2007/030580, focussing on the administration of a CpG oligonucleotide for protecting cells against cytotoxic insult.